Familial dyskinesia and facial myokymia (FDFM): A novel movement disorder

Fernandez, Magali; Raskind, Wendy H.; Wolff, John; Matsushita, Mark; Yuen, Eric; Graf, Wilhelm; Lipe, Hillary; Bird, Thomas D.

doi:10.1002/ana.98

Cited by 52 publications

(82 citation statements)

References 21 publications

(13 reference statements)

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“…9,16 Conversely, we show that dyskinesias were not paroxysmal, but constantly present from the onset of symptoms in the 3 cases we report, albeit markedly influenced by emotional states and action. It is of interest that all 3 cases developed episodes of violent ballistic movements and spasms later during the disease course.…”

Section: Clinical Presentations Of Cases With Pathogenic Adcy5supporting

confidence: 43%

“…3,4 However, a number of families with BHC do not carry mutations in NKX2-1, suggesting that other genes may be responsible for this syndrome. [5][6][7][8] Familial dyskinesia with facial myokymia (FDFM) (OMIM 606703) was first described by Fernandez et al 9 in 2001. They reported a 5-generation kindred with 18 members affected with an autosomal dominant movement disorder, mainly characterized by childhood or early adolescent onset of hyperkinetic movements and perioral and periorbital myokymia.…”

Section: Discussionmentioning

confidence: 99%

“…A distinctive feature of this disorder was the presence of prominent periorbital and perioral facial myokymia. 9 After the identification of ADCY5 as the responsible gene in the original FDFM pedigree, the same group described a second pathogenic missense variant in ADCY5 (c.1252C.T; p.R418W), which occurred de novo in 2 unrelated individuals with a sporadic complex hyperkinetic movement disorder. 16 The phenotype of these cases shared some features with the original FDFM pedigree, but it was more severe and further encompassed delayed motor milestones, axial hypotonia, and progressive gait difficulties in one case.…”

Section: Clinical Presentations Of Cases With Pathogenic Adcy5mentioning

confidence: 99%

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ADCY5 mutations are another cause of benign hereditary chorea

et al. 2015

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Objective: To determine the contribution of ADCY5 mutations in cases with genetically undefined benign hereditary chorea (BHC). Methods:We studied 18 unrelated cases with BHC (7 familial, 11 sporadic) who were negative for NKX2-1 mutations. The diagnosis of BHC was based on the presence of a childhood-onset movement disorder, predominantly characterized by chorea and no other major neurologic features. ADCY5 analysis was performed by whole-exome sequencing or Sanger sequencing. ADCY5 and NKX2-1 expression during brain development and in the adult human brain was assessed using microarray analysis of postmortem brain tissue.Results: The c.1252C.T; p.R418W mutation was identified in 2 cases (1 familial, 1 sporadic).The familial case inherited the mutation from the affected father, who had a much milder presentation, likely due to low-grade somatic mosaicism. The mutation was de novo in the sporadic case. The clinical presentation of these cases featured nonparoxysmal generalized chorea, as well as dystonia in the most severely affected, but no facial myokymia. We observed significant progression of symptoms in ADCY5 mutation carriers, in contrast to BHC secondary to NKX2-1 mutations. The difference in the clinical course is mirrored by the brain expression data, showing increasing ADCY5 expression in the striatum during brain development, whereas NKX2-1 shows an opposite trend.Conclusions: Our study identifies mutations in ADCY5, the gene previously linked to familial dyskinesia with facial myokymia, as a cause of familial and sporadic BHC. ADCY5 genetic analysis should be performed in cases with a benign choreiform movement disorder even in the absence of facial myokymia. Benign hereditary chorea (BHC) (OMIM 118700) is a rare and poorly delineated syndrome, clinically characterized by onset of symptoms in infancy or early childhood, relatively little clinical progression, and absence of other major neurologic deficits, in particular prominent cognitive decline.

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Section: Clinical Presentations Of Cases With Pathogenic Adcy5supporting

confidence: 43%

Section: Discussionmentioning

confidence: 99%

Section: Clinical Presentations Of Cases With Pathogenic Adcy5mentioning

confidence: 99%

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ADCY5 mutations are another cause of benign hereditary chorea

et al. 2015

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“…Clinical descriptions of this family, with essentially the same manifestations as EHC, were published, with detailed descriptions of 7 affected people. 6,12 In 2014, repeat hand and face EMG of IV-4 6 showed frequent involuntary bursts of motor units provoked by needle insertion and volition, similar to those in EHC IV-5. These bursts were not typical of myokymic discharges because they were often stimulus provoked, highly variable in duration, and not rhythmic.…”

Section: Id027 (Pr418w Mosaic)mentioning

confidence: 72%

“…12 Various anxiolytics and antiepileptics have produced no improvement (e.g., chlordiazepoxide, primidone, amitriptyline, trifluoperazine, diphenylhydantoin). Acetazolamide and propranolol have been of modest anecdotal benefit in a few persons.…”

Section: Id027 (Pr418w Mosaic)mentioning

confidence: 99%

ADCY5 -related dyskinesia

et al. 2015

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Objective: To investigate the clinical spectrum and distinguishing features of adenylate cyclase 5 (ADCY5)-related dyskinesia and genotype-phenotype relationship. Methods:We analyzed ADCY5 in patients with choreiform or dystonic movements by exome or targeted sequencing. Suspected mosaicism was confirmed by allele-specific amplification. We evaluated clinical features in our 50 new and previously reported cases.Results: We identified 3 new families and 12 new sporadic cases with ADCY5 mutations. These mutations cause a mixed hyperkinetic disorder that includes dystonia, chorea, and myoclonus, often with facial involvement. The movements are sometimes painful and show episodic worsening on a fluctuating background. Many patients have axial hypotonia. In 2 unrelated families, a p.A726T mutation in the first cytoplasmic domain (C1) causes a relatively mild disorder of prominent facial and hand dystonia and chorea. Mutations p.R418W or p.R418Q in C1, de novo in 13 individuals and inherited in 1, produce a moderate to severe disorder with axial hypotonia, limb hypertonia, paroxysmal nocturnal or diurnal dyskinesia, chorea, myoclonus, and intermittent facial dyskinesia. Somatic mosaicism is usually associated with a less severe phenotype. In one family, a p.M1029K mutation in the C2 domain causes severe dystonia, hypotonia, and chorea. The progenitor, whose childhood-onset episodic movement disorder almost disappeared in adulthood, was mosaic for the mutation.Conclusions: ADCY5-related dyskinesia is a childhood-onset disorder with a wide range of hyperkinetic abnormal movements. Genotype-specific correlations and mosaicism play important roles in the phenotypic variability. Recurrent mutations suggest particular functional importance of residues 418 and 726 in disease pathogenesis. Neurology ® 2015;85:2026-2035 GLOSSARY ADCY5 5 adenylate cyclase 5; ATP 5 adenosine-59-triphosphate; cAMP 5 39,59-cyclic adenosine monophosphate; ChDys 5 chorea-dystonia; EHC 5 essential hereditary chorea; FDFM 5 familial dyskinesia with facial myokymia; MIP 5 molecular inversion probe; SNP 5 single nucleotide polymorphism; STRP 5 short tandem repeat marker.

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Autosomal Dominant Familial Dyskinesia and Facial Myokymia

et al. 2012

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Background: Familial dyskinesia with facial myokymia (FDFM) is an autosomal dominant disorder that is exacerbated by anxiety. In a 5-generation family of German ancestry, we previously mapped FDFM to chromosome band 3p21-3q21. The 72.5-Mb linkage region was too large for traditional positional mutation identification.Objective: To identify the gene responsible for FDFM by exome resequencing of a single affected individual.Participants: We performed whole exome sequencing in 1 affected individual and used a series of bioinformatic filters, including functional significance and presence in dbSNP or the 1000 Genomes Project, to reduce the number of candidate variants. Co-segregation analysis was performed in 15 additional individuals in 3 generations.Main Outcome Measures: Unique DNA variants in the linkage region that co-segregate with FDFM. Results:The exome contained 23 428 single-nucleotide variants, of which 9391 were missense, nonsense, or splice site alterations. The critical region contained 323 variants, 5 of which were not present in 1 of the sequence databases. Adenylyl cyclase 5 (ADCY5) was the only gene in which the variant (c.2176GϾA) was co-transmitted perfectly with disease status and was not present in 3510 control white exomes. This residue is highly conserved, and the change is nonconservative and predicted to be damaging.Conclusions: ADCY5 is highly expressed in striatum. Mice deficient in Adcy5 develop a movement disorder that is worsened by stress. We conclude that FDFM likely results from a missense mutation in ADCY5. This study demonstrates the power of a single exome sequence combined with linkage information to identify causative genes for rare autosomal dominant mendelian diseases.

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Familial dyskinesia and facial myokymia (FDFM): A novel movement disorder

Cited by 52 publications

References 21 publications

ADCY5 mutations are another cause of benign hereditary chorea

ADCY5 mutations are another cause of benign hereditary chorea

ADCY5 -related dyskinesia

Autosomal Dominant Familial Dyskinesia and Facial Myokymia

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